Browsing by Subject "Epigenetics"
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Item Alcohol promotes mammary tumor development through regulation of estrogen signaling(2012-05) Wong, Amy W.; Nuñez, Nomelí P.Breast cancer is the most common malignancy affecting women and the second leading cause of death among women in the United States. Alcohol consumption is one of the few modifiable risk factors for breast cancer development but the mechanism by which it contributes to mammary cancer development and progression remains unclear, although it has been suggested that estrogen is critical for this process. To determine if alcohol promotes mammary tumor development via the estrogen pathway, estrogen receptor alpha-negative (ER[alpha]-negative) MMTV-neu mice were treated with various doses of ethanol and activation of estrogen signaling was measured. Our results showed that alcohol consumption increased estrogen signaling activation, serum estrogen levels and, most interestingly, expression of ER[alpha] in tumor tissue in the ER[alpha]-negative mice. Several lines of evidence in literature suggest that ER[alpha] expression in ER[alpha]-negative cancer cells is inhibited through epigenetic regulation. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than DNA sequence changes. Thus, to determine whether alcohol may regulate ER[alpha] re-expression in ER[alpha]-negative breast cancer cells through epigenetic mechanisms, we examined the effects of ethanol on CpG methylation and histone modifications (acetylation and methylation) of two ER[alpha]-negative breast cancer cell lines, MDA-MB-231 (human) and MMTV-neu (mouse). We also examined whether the epigenetic modifications subsequently affect the recruitment of transcriptional regulation complexes to the ER[alpha] promoter to regulate ER[alpha] transcription. Results showed that alcohol promotes ER[alpha] re-expression in these ER[alpha]-negative cell lines and that this effect was associated with decreased CpG methylation, an overall increase of histone acetylation and decrease of histone methylation, and an alteration in the enrichment of the ER[alpha] transcriptional regulation complexes (pRb2/p130-E2F4/5-HDAC1-SUV39H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1) at the ER[alpha] promoter, which may contribute to cancer cell progression. In addition, we found that the inhibition of ER[alpha] by tamoxifen specifically blocks the effects of alcohol on ER[alpha] reactivation. To determine how alcohol promotes cell invasive ability, a critical process for cancer progression, we examined the role of two genes, metastasis suppressor Nm23 and integrin alpha-5 ITGA5, which we identified to be important for alcohol-induced breast cancer cell invasion. It has previously been shown that estrogen may regulate Nm23 expression and that estrogen regulation may be important for ITGA5-mediated cancer progression. Our results showed that alcohol promotes cancer cell invasion through the down-regulation of Nm23, which led to the subsequent increase of ITGA5 and increase of cell invasion. Collectively, data from my research strongly supports and provides evidence that alcohol promotes breast cancer development and progression through the regulation of estrogen signaling.Item Assessing the preservation of cytosine methylation in ancient DNA from five prehistoric Native American populations(2013-05) Smith, Ricky Wayne Aldon; Bolnick, Deborah Ann; DiFiore, AnthonyCytosine methylation of CpG dinucleotides is an important epigenetic mark that regulates gene expression in humans. While methylation patterns in extant populations have been widely studied, few studies have attempted to analyze methylation in ancient DNA. Indeed, it was only recently shown that methyl groups can be preserved in ancient DNA. However, it is unknown how often methylation patterns can be recovered from ancient samples with preserved nuclear DNA. If they are frequently preserved, it may ultimately be possible to infer patterns of gene activity at the population level in ancient times. In this study, I assessed the preservation of cytosine methylation in ancient DNA from the remains of 30 prehistoric Native Americans from California, Illinois, Kentucky, and Mexico. These samples were previously shown to contain endogenous mitochondrial and nuclear DNA. I analyzed the cytosine methylation states of CpG-rich retrotransposons, which are epigenetically inactivated by cytosine methylation in humans. Unmethylated cytosines were converted to uracils by treatment with sodium bisulfite. Bisulfite products were pyrosequenced, and C-to-T conversions at potentially methylated CpG dinucleotides were quantified. I found that cytosine methylation is readily recoverable from human remains with preserved nuclear DNA from various localities over the time depth tested (~6000 years). This study presents the first direct evidence of cytosine methylation in ancient human remains, and suggests that it may be possible to analyze patterns of gene activity in ancient populations.Item Epigenetics and Trauma(Berkeley Law, University of California, 2020-01) Champagne, FrancesItem Epigenetics of SNCA and APOE Genes and Lewy Body Dementia(2023-04-17) Yesland, MiikoLewy Body Dementia (LBD) is a neurodegenerative disease characterized by rapid cognitive decline, Parkinson's-like motor issues, hallucinations and eventually death. Because LBD displays traits similar to other neurodegenerative conditions, such as Alzheimer's disease (AD), researchers have sought more reliable, specific ways to diagnose LBD. Recent studies have singled out some candidate genes that could serve as potential biomarkers for LBD: SNCA and APOE. Epigenetic modifications, specifically hypomethylation, in SNCA and APOE genes is positively correlated with the development of Lewy Body Dementia, which suggests that these genes could be potential biomarkers to diagnose LBD if their mechanistic contribution to LBD development is better understood.Item Epigenetics, Environments, and the Dynamic Brain(Department of Pharmacology and Center for Biomedical Neuroscience, UT Health San Antonio, 2020-03) Champagne, FrancesItem Genetic and epigenetic mechanisms of adaptation in stony corals(2017-07-26) Dixon, Groves Bayne; Matz, Mikhail V.; Bolnick, Daniel I; Hofmann, Hans A; Iyer, Vishy; Kirkpatrick, MarkIn this dissertation, I used genomic techniques to examine interrelationships between genotype, gene expression, DNA methylation and environmental conditions in the model coral Acropora millepora. I present three major findings: 1) populations in the Great Barrier Reef have the potential for rapid genetic adaptation to climate change 2) patterns of DNA methylation predict gene expression plasticity 3) patterns of DNA methylation can predict fitness under environmental change.Item Genetic networks and epigenetic mechanisms of temperature-dependent sex determination in the red-eared slider turtle, Trachemys scripta(2014-05) Matsumoto, Yuiko; Crews, David; Atkinson, Nigel; Hofmann, Johann; Vokes, Steve; Zakon, HaroldIn the red-eared slider turtle, Trachemys scripta, gonadal sex is determined by the incubation temperature during the mid-trimester of development; temperature effects can be overridden by exogenous ligands if they are administered during the temperature-sensitive period of development. How the physical signal of temperature is transduced into a biological signal that ultimately results in determining gonad sex is not known. My thesis research focuses on five candidate sex determining genes: cyp19a1 (aromatase), Forkhead box protein L2, R-spondin1, Doublesex mab3-related transcription factor 1, and Sex-determining Region on Y chromosome-box 9. The first three genes are markers of ovarian differentiation while the latter two genes are markers of testicular differentiation. Both in ovo (egg) and in vitro (gonadal explants) studies were conducted. Chapters 1 and 2 examine how exogenous steroid ligands interact with candidate genes as the gonads differentiate into testes or ovaries. Topical application of testosterone with aromatase inhibitor to eggs incubating at the female-producing temperature (31 ºC; FPT) suppresses expression of ovarian markers while increasing expression of testicular markers. Administration of 17β-estradiol (E2) to eggs incubating at a male-producing temperature (26 ºC; MPT) increases expression of ovarian markers while testicular markers are suppressed. This suggests that exogenous ligands modify gonadal trajectory by re-directing (suppression and activation) the expression of candidate genes. Chapter 3 identifies the gonad-specific promoter and the temperature-dependent DNA methylation signatures of the aromatase gene during gonadal differentiation. DNA methylation of the aromatase promoter is lowest at FPT relative to MPT. Exogenous E2 and certain polychlorinated biphenyls retain typical methylation patterns observed at MPT (Chapter 4). This suggests that despite the ability of exogenous ligands to alter the transcriptional profiles and gonad phenotypes, the MPT set the temperature typical epigenetic marks first at the beginning of TSP. Recruitment of modified histone proteins, H3K4me3 and H3K27me3, at the aromatase promoter is FPT-specific during gonad determination. Temperature shift experiments suggest a lack of histone enrichment is due to MPT cue, but is not reversible by FPT. Preliminary analysis of modified histones by Next-generation sequencing shows high duplication levels across samples, leaving room for technical improvement in future study.Item Heritable Epigenetic Variation among Maize Inbreds(Public Library of Science, 2011-11-17) Eichten, Steve R.; Swanson-Wagner, Ruth A.; Schnable, James C.; Waters, Amanda J.; Hermanson, Peter J.; Liu, Sanzhen; Yeh, Cheng-Ting; Jia, Yi; Gendler, Karla; Freeling, Michael; Schnable, Patrick S.; Vaughn, Matthew W.; Springer, Nathan M.Epigenetic variation describes heritable differences that are not attributable to changes in DNA sequence. There is the potential for pure epigenetic variation that occurs in the absence of any genetic change or for more complex situations that involve both genetic and epigenetic differences. Methylation of cytosine residues provides one mechanism for the inheritance of epigenetic information. A genome-wide profiling of DNA methylation in two different genotypes of Zea mays (ssp. mays), an organism with a complex genome of interspersed genes and repetitive elements, allowed the identification and characterization of examples of natural epigenetic variation. The distribution of DNA methylation was profiled using immunoprecipitation of methylated DNA followed by hybridization to a high-density tiling microarray. The comparison of the DNA methylation levels in the two genotypes, B73 and Mo17, allowed for the identification of approximately 700 differentially methylated regions (DMRs). Several of these DMRs occur in genomic regions that are apparently identical by descent in B73 and Mo17 suggesting that they may be examples of pure epigenetic variation. The methylation levels of the DMRs were further studied in a panel of near-isogenic lines to evaluate the stable inheritance of the methylation levels and to assess the contribution of cis- and trans- acting information to natural epigenetic variation. The majority of DMRs that occur in genomic regions without genetic variation are controlled by cis-acting differences and exhibit relatively stable inheritance. This study provides evidence for naturally occurring epigenetic variation in maize, including examples of pure epigenetic variation that is not conditioned by genetic differences. The epigenetic differences are variable within maize populations and exhibit relatively stable trans-generational inheritance. The detected examples of epigenetic variation, including some without tightly linked genetic variation, may contribute to complex trait variation.Item Investigating the relationship between stress and the epigenome(2023-08-11) Miller, Melissa P. H.; Champagne, Frances; Fonken, Laura; Hofmann, Johann; Goosby, BridgetLifetime stress exposure has profound effects on neurobiology with lifelong implications for mental health. Epigenetic processes, such as DNA methylation, have been proposed as playing a role in shaping the trajectories of stress-related disorders such as major depression and posttraumatic stress disorder, yet the relationship between stress and DNA methylation has yet to be evaluated in depth. The research presented in this thesis aimed to evaluate 1) the factors associated with chronic biological stress, 2) the relationship between chronic biological stress and DNA methylation, 3) and the impact of acute psychological stress on DNA methylation. Chapters 3 and 4 of this thesis utilized human subjects to investigate the complexity of hair cortisol as a biomarker of chronic stress and its relationship with the epigenome. Results from these studies indicate that chronic biological stress is subtly influenced by both demographic and psychological factors, possibly in a sex-dependent manner. We also report many DNA methylation sites across the genome that are associated with chronic biological stress. Chapter 5 of this thesis aimed to determine the impact of acute stress on the epigenome in humans using a controlled laboratory experiment. For the first time in the literature, we test the influence of acute psychological stress on genome-wide DNA methylation and report novel sites related to stress and immune function that may be sensitive to acute stress, and that are implicated in chronic stress. Taken together, these studies link acute and chronic stress, support the notion that both short- and long-term stress have epigenetic impact, and inform the mechanism of psychopathology. The specific molecular processes by which different types of stress promote epigenetic changes across the lifespan and contribute to the differential susceptibility of males and females to psychiatric morbidity require further investigation.Item Investigation of the proteomic interaction profile of uncoupling protein 3 and its effect on epigenetics(2014-08) Yan, Xiwei; Mills, Edward MichaelUncoupling proteins (UCPs) are localized on the inner mitochondrial membrane (IMM) and “uncouple” the electrochemical proton gradient formed by the electron transport chain (ETC) from ATP production. Though the prototypical uncoupling protein 1 (UCP1) is known to mediate the cold-induced thermogenesis in rodents and human neonates, the physiological and biochemical functions of the homologs UCP2-5 are still under debate. Our research focuses on UCP3, the homolog prevalently expressed in skeletal muscle (SKM), the most important metabolic organs. UCP3 has long been speculated to have a pivotal role in maintaining the mitochondrial metabolism. Several biochemical roles have been attributed to UCP3, including the regulation of fatty-acid transport and oxidation, reactive oxygen species (ROS) scavenging and calcium uptake. And several proteins have been identified to directly bind with UCP3 and facilitate its function. But to further understand how UCP3 relates to different aspects of mitochondrial functions, a more comprehensive profile of the UCP3 interaction partners is needed. We performed a mass spectrometry-based experiment and successfully identified a list of over 170 potential proteins that may directly or indirectly interact with UCP3, and several novel functions of UCP3 are implied by these protein-protein interactions. Additionally, researches have shown that the metabolic defects are important contributing factors to the epigenetic changes. Considering the roles of UCP3 in sustaining the normal mitochondrial metabolism, we hypothesized that UCP3 has a novel function in regulating the genomic DNA methylation processes. The data we obtained from the pilot study confirms that loss of UCP3 will lead to aberrant DNA methylation changes. But further experiment is still needed to investigate the regulatory pathway between UCP3 and DNA methylation. The physiological role of UCP3 in defending against cancer, diabetes and obesity has been investigated, but the mechanisms how UCP3 protect the organism from these diseases have not been elucidated. Our research sheds light on the understanding of UCP3 functions and may be of significant therapeutic benefit in the prevention and treatment of these diseases.Item Mechanisms underlying vernalization-mediated VERNALIZATION INSENSITIVE 3 (VIN3) induction in Arabidopsis thaliana(2013-05) Zografos, Brett Robert; Sung, SibumVernalization is defined as the response to prolonged cold exposure required for acquiring the molecular competence necessary to undergo floral transition. FLOWERING LOCUS C (FLC), a potent floral repressor in Arabidopsis, is highly expressed before vernalizing cold treatment but is repressed during prolonged vernalization. VERNALIZATION INSENSITIVE 3 (VIN3) is a Plant HomeoDomein (PHD)- containing protein that is required for establishing vernalization-mediated repression of FLC. The induction of VIN3 is one of the earliest molecular events in vernalization response and its expression is intimately linked to prolonged cold exposure. However, mechanisms underlying VIN3 induction remain poorly understood. The constitutive repression of VIN3 in the absence of cold is due to multiple repressive components, including a transposable element-derived sequence, LIKE-HETEROCHROMA TIN PROTEIN 1 (LHP1), and POLYCOMB REPRESSION COMPLEX 2 (PRC2). Furthermore, the full extent of VIN3 induction by vernalization requires activating complex components, including EARLY FLOWERING 7 (ELF7) and EARLY FLOWERING IN SHORT DAYS (EFS). Dynamic changes in the histone modifications present at VIN3 chromatin during vernalization were also observed, indicating that chromatin changes play a critical role in regulating VIN3 induction. However, VIN3 induction by vernalization still occurs in the absence of activation complexes and de- repression of VIN3 in the absence of the repressive complexes is not sufficient for achieving complete induction. Thus, unknown cold-influenced regulators responsible for achieving maximum VIN3 induction during vernalization must exist. Therefore, forward genetic screening was undertaken to elucidate upstream regulators of VIN3. Molecular characterization of T-DNA mutant populations elucidated two interesting mutants: a mutant that ectopically expressed VIN3 before cold (ectopic VIN3 induction, evi1) and mutants that failed to induce VIN3 during vernalization (defects in VIN3 induction, dvi1). FLC is over-expressed in dvi1 despite its failure to induce VIN3 expression during vernalization, suggesting that this mutant may regulate both VIN3 and FLC. In evi1, FLC is hyper-repressed after 40 days of vernalization, leading to an acceleration of flowering time. These results indicate that regulators of VIN3 in the vernalization pathway exist and that these regulators may use different mechanisms in order to influence VIN3 expression.Item Parental Epigenetic Influences Within and Across Generations(Neuroscience Program Seminar, University of Illinois, Urbana-Champaign, 2019-11) Champagne, FrancesItem Phenotypes and mechanisms of epigenetic transgenerational inheritance due to prenatal exposure of endocrine disrupting chemicals(2018-05) Gillette, Ross; Crews, David; Gore, Andrea C; Atkinson, Nigel S; McCarrey, John RNearly all humans and animals carry a measurable body burden of endocrine disrupting chemicals (EDCs), which interfere with or alter endogenous hormone signaling and cause various disease phenotypes depending on their composition, dose, and period of exposure. Furthermore, EDCs impart deleterious phenotypes on multiple generations without subsequent exposure. The inheritance of diseased phenotypes is believed to be the result of heritable mutations to the epigenome (epimutations) within the germline. It is essential that we understand how EDC exposure affects mammals and that we identify the mechanisms responsible for inheritance. It is the goal of this dissertation to describe and test the phenotypes associated with the transgenerational inheritance of epimutations due to two representative but common categories of EDCs; estrogenic – polychlorinated biphenyls (PCBs) and anti-androgenic – vinclozolin. To achieve this, I used a multidisciplinary and systems biology approach across animal behavior, physiology, brain metabolism, neural gene expression, and genetic sequencing. Pregnant dams were injected with vinclozolin, PCBs, or a vehicle control during mid to late gestation. The resulting generation was bred to obtain the F2 and F3 generation without further exposure. To understand how a diseased past might interact with a troubled present, ancestral EDC exposure was challenged with chronic restrain stress (CRS) during puberty. Last, both male and female animals were subjected to treatment to determine how development and different hormonal milieus altered the outcome. I found that ancestral exposure to vinclozolin decreased anxiety behavior, increased body weight, and altered the metabolic capacity of brain nuclei involved in anxiety behaviors. Exposure to CRS often exacerbated these effects. Gene expression analysis within discrete nuclei of the brain identified neural proliferation factors, thermoregulatory genes, and epigenetic machinery was altered by ancestral vinclozolin exposure. Males and females differed in their response to ancestral vinclozolin exposure and CRS; the hippocampus is more vulnerable in females and the amygdala is more vulnerable in males. Prenatal PCB exposure increased body weight in males and females but only affected anxiety behavior in males. Last, direct and ancestral exposure to vinclozolin and PCBs caused epimutations in the germline and brain of males. Substantial over lap in the affected sites suggest a common mechanism of interaction between EDCs and the epigenome.Item Regulation of the DNA methylome in models of alcohol use disorders(2018-08-08) Tulisiak, Christopher Thomas; Harris, R. Adron; Ponomarev, Igor, Ph. D.; Atkinson, Nigel S.; Gore, Andrea C.; Iyer, Vishwanath R.Alcohol use disorder (AUD) is a highly prevalent and pernicious substance use disorder that is characterized by widespread changes to gene expression that may drive maladaptive behavioral progression from binge alcohol use to dependence and withdrawal. The prefrontal cortex (PFC) in mice and superior frontal cortex (SFC) in humans undergo changes in gene expression and function after chronic alcohol and are known to drive late-stage AUD behaviors. Epigenetic regulatory mechanisms are mediating factors between environment and gene expression. Because DNA-level epigenetic regulation of CpG dinucleotides is known to contribute to gene expression and disease pathology, I hypothesized that chronic alcohol exposure alters the global DNA-level epigenetic landscape, leading to changes in expression of genes that contribute to alcohol pathologies. In the first chapter, I provide a comprehensive review of the literature pertaining to DNA modifications and their role in AUD. In the second chapter, I use a mouse model of alcohol intoxication, dependence, and withdrawal to identify the effects of chronic alcohol on DNA-level epigenetic regulatory systems in the PFC and report that expression of DNA-modifying genes is dynamically regulated by alcohol exposure and withdrawal, and this regulation leads to downstream changes in global DNA methylation and hydroxymethylation. These changes are cell type-specific and are influenced not only by time since alcohol exposure, but also by sex. In the third chapter, I analyzed a human methylation microarray dataset to describe alcohol- and sex-related differential methylation in the genome. From this analysis, I present differential methylation in genes of molecular pathways involved in known contributing factors to AUD, including neuroimmune pathways and neuronal signaling and function, and describe how these changes to DNA methylation may contribute to gene expression and AUD phenotype. In the fourth chapter, I describe how normally epigenetically silenced genomic repeats are derepressed and propose a mechanism for how they may contribute to AUD-related neuroinflammation. I conclude by submitting that DNA-level epigenetic regulation is a significant contributor to AUD pathology and suggest that DNA modifications may be a potential therapeutic target requiring continued research into its functional role in regulating alcohol behaviors through mediation between genome and environmentItem Roles for polyploidy, circadian rhythms, and stress responses in hybrid vigor(2014-05) Miller, Marisa Elena; Chen, Z. JeffreyHybrid plants and animals, like corn and the domestic dog, grow larger and more vigorously than their parents, a common phenomenon known as hybrid vigor or heterosis. In hybrids between Arabidopsis ecotypes or species (in allotetraploids), altered expression of circadian clock genes leads to increased starch and chlorophyll content and greater biomass. In plants and animals, circadian clock regulation plays a key role in optimizing metabolic pathways, increasing fitness, and controlling responses to biotic and abiotic stresses. In the allotetraploids, the increased level of heterosis is likely caused by interspecific hybridization as well as genome doubling. However, it is unknown how genome dosage and allelic effects influence heterosis, and whether additional clock output traits, such as stress responses, are altered in hybrids. In three related projects, the effects of genomic hybridization (including parent-of-origin effects) and genome dosage on heterosis were elucidated. In my first project, I found that although ploidy influenced many traits, including seed and cell size, biomass and circadian clock gene expression were most strongly influenced by hybridization. Additionally, parent-of-origin effects between reciprocal hybrids were frequently observed for many traits. In my second project, I described a unique role for RNA-directed DNA methylation (mainly CHH methylation) in mediating the parent-of-origin effect on expression of the circadian clock gene CCA1 in reciprocal hybrids. Altered CCA1 expression peaks were associated with heterosis of biomass accumulation in the reciprocal hybrids. Lastly, I used transcriptome sequencing in hybrids at different times of day to examine changes in downstream clock-regulated pathways. In the hybrids, many genes in photosynthetic pathways were upregulated, while many genes involved in biotic and abiotic stresses were repressed during the morning and afternoon, respectively. Additionally, natural variation between parents in stress-responsive gene expression was found to be crucial for producing vigorous hybrids. These conceptual advances increase the mechanistic understanding of heterosis, and may guide selection of parents for making better hybrids.Item The evolutionary ecology of phenotypic variance(2023-08-11) Peterson, Christopher R.; Matz, Mikhail V.; Bolnick, Daniel; Farrior, Caroline E; Keitt, Timothy HIndividual variation lies at the foundation of evolutionary theory. Trait differences among individuals can drive ecologically significant changes in the abundance, distribution, and composition of populations and communities. Phenotypic variance is particularly relevant in the context of global change, where plasticity can buffer evolutionary responses to novel conditions. In this dissertation, I investigate the effects, changes, and potential mechanisms of phenotypic variation as they relate to invasion and responses to climate change. In chapter 1, I use a theoretical approach to consider how trait variance affects the eco-evolutionary outcomes of a predator invasion. For chapter 2, I use meta-analysis to examine how trait means and variances change during range expansions. Finally, for chapter 3 I use *Acropora* coral investigate the intergenerational heritability of DNA methylation, a potential mechanism behind phenotypic plasticity.Item What remains : genetic and epigenetic correlates of sociopolitical change and the ulterior traces of power(2017-08) Smith, Ricky Wayne Aldon; Bolnick, Deborah Ann; TallBear, Kimberly; Non, Amy; Tung, Tiffiny; Covey, Ronald; DiFiore, Anthony FRecent developments in queer and feminist materialisms have offered productive ways to rethink the connections between nature and culture, and how these forces are mutually entailed in the constitution of bodies. These insights hold radical potentials for reconfiguring what science can mean and for remaking the worlds it helps to materialize. However, such perspectives are rarely taken as entry points for the production of scientific knowledge. Drawing upon emerging scholarship from queer, feminist, and indigenous theorists, this dissertation aims to take on the genetics lab as a site of political transformation. Here, I develop and apply new approaches for recovering the genetic and epigenetic correlates of sociopolitical change, showing that bodies are a “shifting entanglement of relations” (Barad 2007) between sociopolitical and material forces. I begin by evaluating the boundary-making practices and conditions of possibility through which the field of population genetics has materialized certain indigenous bodies and histories to the exclusion of others. This research demonstrates how conventional population genetic research in North America, long predicated on notions of “biological purity”, has helped to maintain the sociopolitical conditions of the settler state. Working from tribal and First Nations self-definitions, this research brings attention to histories that have been hidden in previous population genetic studies in the Americas. This work further destabilizes notions of “indigenous DNA” as the sole criteria for indigenous belonging, through which settler claims to indigenous bodies and cultural heritage have unfolded in recent decades (TallBear 2013). Next, I developed and evaluated methods for reconstructing chemical modifications to DNA, known as cytosine methylation, in five ancient genomes. Because changes in methylation can be shaped by social and environmental factors, reconstructing cytosine methylation in DNA from ancient people could help recover aspects of their lived experiences, shedding new light on past lifeways. I applied paleoepigenetic approaches to evaluate archaeologically-informed questions about the Wari society, the first expansive state in the central Peruvian Andes. By reconstructing ancient methylation patterns from 14 individuals who lived before and after the decline of the Wari state, I show that changes in DNA methylation trace sociopolitical and environmental changes in the ancient world.